Y-family DNA polymerase (Y-family Pols)

Y-family DNA polymerases are a specialized group of enzymes, including Pol eta, Pol iota, Pol kappa, and Rev1, that facilitate translesion synthesis (TLS), a critical DNA damage tolerance mechanism (Yang, 2014). Unlike high-fidelity replicative polymerases, Y-family members possess a spacious and flexible active site that allows them to bypass bulky DNA lesions, such as UV-induced thymine dimers or platinum-based chemotherapy adducts, which would otherwise stall replication forks (Sale, 2013). While this process ensures cell survival by allowing replication to complete, it is inherently error-prone and is a primary driver of both spontaneous and damage-induced mutagenesis (Ghosal & Chen, 2013). In oncology, the overexpression of these polymerases is a major factor in chemoresistance, as they enable cancer cells to tolerate and recover from DNA-damaging treatments like cisplatin (Zhu et al., 2016). Consequently, they are being actively explored as therapeutic targets, with small molecules like JH-RE-06 designed to inhibit their function and sensitize tumors to conventional therapies (Wojtaszek et al., 2019). Deficiencies in specific family members, most notably Pol eta, are the underlying cause of Xeroderma pigmentosum variant (XPV), highlighting their essential role in protecting against UV-induced genomic instability (Masutani et al., 1999). In addition to their role in eukaryotes, bacterial homologs like DinB and UmuC contribute to antibiotic resistance and stress-induced mutagenesis, making them potential targets for novel antimicrobial strategies (Naiman et al., 2014).

Other names

Translesion synthesis polymerasesTLS polymerasesDinB-like polymerasesUmuC-like polymerasesDNA polymerase etaDNA polymerase iotaDNA polymerase kappaDNA polymerase rev1

Inhibition of translesion synthesis (TLS) by blocking the activity or recruitment of Y-family polymerases to DNA lesion sites, thereby preventing the bypass of chemotherapy-induced DNA damage and sensitizing cancer cells to apoptosis (Wojtaszek et al., 2019).